The prevalence of diabetes for all age groups worldwide was estimated to be 2.8%, or 171 million in 2000, and is projected to be 4.4%, or 366 million in 2030. See Wild et al., 2004, Diabetes Care 27(5): 1047-1053. In the United States alone, the prevalence of diabetes mellitus in 2005 was estimated at 20.8 million, or roughly 7% of the U.S. population. See Centers for Disease Control and Prevention, 2005, National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2005. Approximately 95% of all patients with diabetes mellitus have type II disease. Diabetes is currently the fifth leading cause of death in the United States and is associated with excess morbidity stemming from cardiovascular disease, kidney failure, blindness, and lower limb amputation.
Similarly, obesity is a condition increasingly affecting the population worldwide. According to the World Health Organization, in 1995 there were an estimated 200 million obese adults worldwide and another 18 million under-five children classified as overweight. As of 2000, the number of obese adults had increased to over 300 million. See Formiguera et al., 2004, Best Practice & Research Clinical Gastroenterology, 18:6, 1125-1146.
The insulinotropic peptides glucagon-like peptide (GLP-1), exendin-3 and exendin-4 have been investigated as possible therapeutic agents for the management of type II non-insulin-dependent diabetes mellitus as well as related metabolic disorders, such as obesity. GLP-1 is a proglucagon-derived peptide secreted from intestinal L-cells in response to nutrient ingestion. GLP-1 acts as an incretin to lower postprandial glycemic excursion via stimulation of insulin secretion and inhibition of glucagon secretion. GLP-1 also exerts actions independent of islet hormone secretion, including inhibition of both gastric emptying and food intake and stimulation of β-cell proliferation. As GLP-1 agonists, exendin-3 and exendin-4 mimic the actions of naturally occurring GLP-1 and are therefore classified as incretin mimetics.
While useful, GLP-1, exendin-3 and exendin4 can present limited duration of action associated with short plasma half-lives in vivo, mainly due to rapid serum clearance and proteolytic degradation by dipeptidyl peptidase-IV. In addition, administration of these peptides for the treatment of diabetes or obesity can result in nausea side effect. Subcutaneous injection of GLP-1 at high doses (1.5 nmol/kg body weight and higher) lead to nausea and, less often, vomiting in a significant proportion of subjects exposed to treatment. See Ritzel et al., 1995, Diabetologia 38:720-725. Further, in three phase III comparative efficacy trials of exenatide, the synthetically derived peptide of exendin-4, nausea was the most commonly reported adverse event, with an incidence of 43.5% of the 1446 enrolled patients enrolled in all three studies. See Iltz et al, 2006, Clin. Ther. 28(5): 652-665.
Thus, there is a need for administration of forms of GLP-1, exendin-3, exendin-4, and other insulinotropic peptides which minimize side effects such as nausea and vomiting, but maintain their therapeutic advantages.